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Summary Table

Category	Detail
Risk Factors	Healthcare workers with unprotected exposure to SARS patients; travelers to or residents of endemic areas (Southern China, Hong Kong, Singapore, Toronto during the 2002-2003 outbreak); close household contacts of confirmed SARS cases; laboratory personnel handling SARS-CoV specimens without proper biosafety precautions
Etiology	SARS-associated coronavirus (SARS-CoV), a novel betacoronavirus; zoonotic origin from horseshoe bats (Rhinolophus spp.) with palm civets (Paguma larvata) as the probable intermediate host
Patient Presentation	Acute onset of high fever (>38.0 C), often as the first symptom, followed by dry nonproductive cough, progressive dyspnea, myalgia, headache, and malaise; watery diarrhea occurs in a subset of patients during the second week of illness
Classic Physical Exam	Fever with rigors; tachypnea; basilar crackles on lung auscultation; absence of upper respiratory tract signs (no rhinorrhea, no sore throat in most cases); relative bradycardia may be observed
Key Diagnostic Results	Chest radiograph: unilateral or bilateral ground-glass opacities progressing to consolidation; Labs: lymphopenia (often <1,000 cells/microL), elevated LDH, elevated hepatic transaminases (AST/ALT), elevated creatine kinase; RT-PCR positive for SARS-CoV RNA; seroconversion on paired sera by ELISA or immunofluorescence assay (IFA)
Management	Strict airborne plus contact isolation; supportive care with supplemental oxygen; mechanical ventilation with lung-protective strategy for ARDS; no proven antiviral therapy (ribavirin was used empirically without confirmed benefit); systemic corticosteroids were administered in some protocols for progressive disease, though efficacy remains debated
Keywords	"Returned from Southeast Asia with high fever and dry cough," "healthcare worker with febrile respiratory illness after unprotected patient contact," "lymphopenia with bilateral ground-glass opacities," "atypical pneumonia with no upper respiratory symptoms," "rapidly progressive respiratory failure in a cluster of healthcare workers"

WHO Case Definition for SARS

The World Health Organization established a tiered surveillance case definition during the 2003 outbreak. This classification is a testable framework because vignettes may present incomplete data and ask you to categorize the patient.

Classification	Criteria
Suspect Case	Fever ≥38.0 C AND one or more symptoms of lower respiratory tract illness (cough, difficulty breathing, shortness of breath) AND one or more of the following: (a) close contact with a person diagnosed with SARS within 10 days before symptom onset, or (b) history of travel to a WHO-designated affected area within 10 days before symptom onset, or (c) residence in a WHO-designated affected area
Probable Case	A suspect case with chest radiograph findings of pneumonia or respiratory distress syndrome OR a suspect case with autopsy findings consistent with the pathology of ARDS without an identifiable cause OR a person with an unexplained acute respiratory illness resulting in death, with autopsy findings of ARDS without an identifiable cause, who had an epidemiologic link to SARS
Laboratory-Confirmed Case	A person with symptoms and signs clinically suggestive of SARS plus positive laboratory results for SARS-CoV by one or more of the following: (1) RT-PCR positive on at least two separate clinical specimens or the same specimen tested twice, (2) seroconversion by ELISA or IFA (negative antibody on acute serum, positive on convalescent serum), (3) virus isolation in cell culture with confirmatory PCR

Note the WHO definition is hierarchical. A suspect case becomes probable based on imaging or autopsy. A confirmed case requires laboratory evidence. Many exam questions test whether you can distinguish a "probable" from a "confirmed" case when the vignette gives you only radiology without lab confirmation.

1. Pathophysiology

SARS-CoV is an enveloped, positive-sense, single-stranded RNA virus belonging to the genus Betacoronavirus. The virus enters the human respiratory tract via respiratory droplets and close-contact transmission. The critical molecular event is the binding of the viral spike (S) glycoprotein to the angiotensin-converting enzyme 2 (ACE2) receptor, which is expressed abundantly on type II pneumocytes in the lower respiratory tract. This receptor tropism explains why SARS predominantly causes lower respiratory disease rather than upper airway symptoms. The relative scarcity of ACE2 receptors in the nasopharynx is the reason patients typically do not present with rhinorrhea or pharyngitis, which is a classic distinguishing feature from common upper respiratory infections.

After viral entry and replication within the alveolar epithelium, the host immune response triggers a cascade of proinflammatory cytokines, including IL-1, IL-6, IL-8, TNF-alpha, and interferon-gamma. This cytokine storm leads to recruitment of neutrophils and monocytes into the alveolar space, causing diffuse alveolar damage (DAD). Histologically, the lungs show hyaline membrane formation, desquamation of pneumocytes, and interstitial edema. This is the pathologic correlate of the ground-glass opacities seen on chest imaging and the progressive hypoxemia observed clinically.

The lymphopenia that defines SARS on laboratory testing is caused by two mechanisms: (1) direct viral infection and apoptosis of lymphocytes, particularly CD4+ and CD8+ T cells, and (2) cytokine-mediated redistribution and destruction of lymphocytes. Elevated LDH reflects widespread tissue injury, while the rise in hepatic transaminases and creatine kinase indicates extrapulmonary viral dissemination and multiorgan involvement. Gastrointestinal symptoms, particularly watery diarrhea, result from viral replication in enterocytes of the small and large intestine, where ACE2 is also expressed. This explains why stool specimens can be RT-PCR positive and why fecal-oral transmission was documented in certain outbreak clusters (notably the Amoy Gardens outbreak in Hong Kong).

The progression to acute respiratory distress syndrome (ARDS) occurs in approximately 20 to 30 percent of patients, typically during the second week of illness, and represents the leading cause of death. The case fatality rate was approximately 9.6% globally, but rose substantially in patients over 60 years of age (approaching 50% in some cohorts), making advanced age the strongest predictor of mortality.

2. Clinical Manifestation and Classification

SARS follows a triphasic clinical course. Understanding this timeline is critical because exam vignettes often place the patient at a particular phase and ask you to predict the next clinical event or choose the appropriate intervention.

Phase	Timeline	Key Features
Phase 1: Viral Replication (Febrile Prodrome)	Days 1 to 7	High fever (often >38.5 C with rigors), myalgia, headache, malaise, anorexia; minimal or absent respiratory symptoms; viral load is rising; chest radiograph may still be normal or show subtle unilateral opacity
Phase 2: Immune Hyperactivity (Respiratory Deterioration)	Days 8 to 14	Recurrence of fever after brief improvement, onset of dry cough, progressive dyspnea, worsening hypoxemia; chest radiograph shows bilateral ground-glass opacities or consolidation; watery diarrhea may appear; lymphopenia deepens; LDH and transaminases peak
Phase 3: ARDS / Resolution	Day 14 onward	Approximately 20-30% of patients progress to ARDS requiring mechanical ventilation; remainder begin gradual recovery; pulmonary fibrosis may develop as a long-term sequela in survivors

Severity Stratification

Severity	Description
Mild	Fever and constitutional symptoms only; chest radiograph normal or minimally abnormal; $SpO_2$ >95% on room air
Moderate	Pneumonia evident on imaging; $SpO_2$ 90-95% on room air; supplemental oxygen required but no ICU admission
Severe	Meets criteria for ARDS ($PaO_2/FiO_2$ ratio ≤200 mmHg with bilateral infiltrates not explained by cardiac failure); requires mechanical ventilation; may develop multiorgan dysfunction

Additional clinical findings worth noting for vignette recognition: Absence of upper respiratory symptoms (no coryza, no sore throat) in the presence of a febrile lower respiratory illness is a red flag for SARS and other atypical pneumonias. Relative bradycardia (pulse-temperature dissociation) may also be seen. In pediatric patients, the disease tends to follow a milder course compared to adults.

3. Diagnostic Workup

Test	Role	Timing	Key Findings
Chest Radiograph	Best initial imaging	At presentation and serial follow-up	Unilateral ground-glass opacity progressing to bilateral consolidation; peripheral predominance; pleural effusion is rare
High-Resolution CT (HRCT) Chest	More sensitive for early disease	When CXR is normal but clinical suspicion is high	Ground-glass opacities, interlobular septal thickening, air-space consolidation; subpleural and lower lobe predominance
RT-PCR (SARS-CoV RNA)	Confirmatory molecular test	Nasopharyngeal aspirate, stool, or serum; best yield after day 5 of illness	Positive in respiratory specimens, stool, and sometimes blood; sensitivity increases with disease duration and with lower respiratory specimens (BAL, sputum)
Serology (ELISA / IFA)	Confirmatory serologic test	Acute serum (within first week) and convalescent serum (day 28 or later)	Seroconversion (fourfold rise in antibody titer or negative-to-positive conversion); IgG typically detectable by day 10 to 14
Viral Culture	Reference standard but impractical	Requires BSL-3 or BSL-4 laboratory	Isolation of SARS-CoV from clinical specimens with confirmatory PCR; not used for routine diagnosis due to biosafety constraints and turnaround time
Complete Blood Count	Screening laboratory test	At presentation	Lymphopenia (<1,000 cells/microL in most patients); thrombocytopenia may also occur
Biochemistry Panel	Supportive	At presentation and serial monitoring	Elevated LDH, elevated AST and ALT, elevated creatine kinase; hyponatremia in some cases

The best initial test in a patient presenting with febrile respiratory illness and an epidemiologic link is a chest radiograph combined with basic laboratory studies (CBC with differential, LDH, hepatic panel). The chest radiograph is essential not only for diagnosis but also for WHO case classification: a suspect case with radiographic pneumonia becomes a probable case.

The most accurate (confirmatory) test is RT-PCR for SARS-CoV RNA. However, there is an important caveat that is highly testable: RT-PCR sensitivity is low in the first 5 days of illness because the viral load in upper respiratory specimens has not yet peaked. During Phase 1, a single negative RT-PCR does not rule out SARS. This is why the WHO requires PCR positivity on at least two specimens or two separate runs to confirm the diagnosis. Lower respiratory tract specimens (bronchoalveolar lavage, induced sputum) have higher sensitivity than nasopharyngeal swabs.

Serology serves as the retrospective confirmatory method. A fourfold rise in IgG titer between acute and convalescent sera (collected at least 21 to 28 days apart) confirms the diagnosis. Serology is not useful for early clinical decision-making but is essential for epidemiologic surveillance and for confirming cases where PCR was negative or indeterminate.

HRCT of the chest is more sensitive than plain radiography for detecting early ground-glass changes and should be considered when clinical suspicion is high but the initial chest radiograph appears normal. The classic CT appearance is multifocal ground-glass opacities with peripheral and lower lobe predominance, which may progress to consolidation.

A key teaching point: the diagnostic workup and the infection control response must happen simultaneously. You do not wait for laboratory confirmation before initiating airborne and contact isolation. If the vignette asks "what is the next best step" in a febrile healthcare worker returning from an outbreak area, the answer is isolate the patient first, then order tests.

4. Management and Treatment

Setting	Intervention	Details
Infection Control	Airborne + Contact + Standard Precautions	N95 respirator (or equivalent), gown, gloves, eye protection; negative-pressure isolation room; this is the single most important intervention and the most testable management point
Supportive Care (Mild-Moderate)	Supplemental oxygen, IV fluids, antipyretics	Target $SpO_2$ ≥93%; acetaminophen for fever; monitor for clinical deterioration with serial chest imaging and oximetry
Severe Disease / ARDS	Mechanical ventilation with lung-protective strategy	Tidal volume 6 mL/kg of predicted body weight; plateau pressure <30 cmH2O; conservative fluid strategy; prone positioning if $PaO_2/FiO_2$ <150 mmHg
Empiric Antimicrobials	Broad-spectrum antibiotics	Cover community-acquired pneumonia organisms (including atypical coverage with a fluoroquinolone or macrolide) until bacterial etiology is excluded; SARS is a diagnosis of exclusion in the acute setting
Ribavirin	Antiviral (empiric, unproven)	Was used at 400 mg IV every 8 hours or 1200 mg orally every 8 hours in some treatment protocols during the 2003 outbreak; multiple studies failed to demonstrate survival benefit; significant toxicity including hemolytic anemia limits its use; not currently recommended
Systemic Corticosteroids	Immunomodulation (controversial)	Methylprednisolone 1 to 2 mg/kg/day IV was used during Phase 2 in some centers to blunt the cytokine storm; timing and dosing were never standardized in controlled trials; early use may prolong viral replication; no definitive evidence of benefit
Convalescent Plasma	Passive immunotherapy	Used in a limited number of patients during the outbreak; observational data suggested a possible reduction in mortality when administered early (before day 14); never studied in a randomized controlled trial for SARS

Step 1: Suspect and Isolate. The moment a vignette describes a febrile patient with lower respiratory symptoms and a relevant epidemiologic link (travel to an affected area, contact with a SARS patient, healthcare worker in an outbreak facility), the first action is to place the patient in airborne isolation in a negative-pressure room with full personal protective equipment for all entering personnel. This is the "next best step" answer in nearly every early-management question.

Step 2: Diagnostic Workup. Obtain chest radiograph, CBC, comprehensive metabolic panel including LDH and hepatic enzymes, blood cultures, sputum for Gram stain and culture, nasopharyngeal aspirate for SARS-CoV RT-PCR, and paired serum for serology (store acute-phase serum for later comparison). Administer empiric antibiotics to cover community-acquired pneumonia, as SARS cannot be clinically differentiated from bacterial pneumonia on presentation alone.

Step 3: Supportive Care and Monitoring. Administer supplemental oxygen to maintain saturation at or above 93%. Serial monitoring of pulse oximetry and chest radiography every 24 to 48 hours during the first two weeks is essential because clinical deterioration typically occurs during Phase 2. If the patient's oxygen requirement is increasing, escalate to high-flow nasal cannula or noninvasive ventilation with extreme caution (these are aerosol-generating procedures and require enhanced infection control measures).

Step 4: ARDS Management. If the patient meets Berlin criteria for ARDS ($PaO_2/FiO_2$ ≤300 mmHg with bilateral opacities and the respiratory failure is not fully explained by cardiac failure or fluid overload), initiate lung-protective mechanical ventilation. Low tidal volumes (6 mL/kg predicted body weight), plateau pressures below 30 cmH2O, and a conservative fluid strategy are the evidence-based standard. Prone positioning for 12 to 16 hours per day should be implemented if the $PaO_2/FiO_2$ remains below 150 mmHg. Intubation is a high-risk aerosol-generating procedure; the team performing it must use powered air-purifying respirators (PAPRs) or equivalent.

Step 5: Notification. SARS is an internationally notifiable condition under the International Health Regulations (IHR 2005). Reporting to local public health authorities and the WHO is mandatory. Contact tracing and quarantine of exposed individuals for 10 days (the maximum incubation period) must be initiated immediately.

Contraindications and Cautions: Ribavirin is contraindicated in pregnancy (Category X) due to teratogenicity and in patients with significant renal impairment (creatinine clearance <50 mL/min) because it is renally cleared and causes dose-dependent hemolytic anemia. Corticosteroids should be avoided in the early viremic phase (Phase 1) as they may impair viral clearance and prolong the period of infectivity.

5. Differential Diagnosis and Distractors

Differential	Why It Is Similar	Key Discriminator
Influenza (Seasonal)	Acute onset of high fever, myalgia, dry cough, and respiratory distress in severe cases	Influenza typically presents with prominent upper respiratory symptoms (rhinorrhea, sore throat) and does not classically cause lymphopenia; rapid influenza diagnostic test or PCR will be positive; no epidemiologic link to SARS-affected area
Avian Influenza (H5N1)	Severe viral pneumonia progressing to ARDS; high case fatality rate; travel history to affected region (Southeast Asia)	Exposure history involves direct contact with poultry or birds rather than person-to-person healthcare/household contact; H5N1 PCR positive; lymphopenia is present in both, but H5N1 has a higher case fatality rate (~60%)
MERS-CoV	Coronavirus-related severe respiratory illness; ACE2-related tropism (though MERS uses DPP4/CD26); high fatality rate; healthcare-associated outbreaks	Epidemiologic link involves travel to the Arabian Peninsula or contact with dromedary camels; MERS-CoV PCR differentiates; MERS has a higher case fatality rate (~35%) but lower transmissibility than SARS
COVID-19 (SARS-CoV-2)	Closely related coronavirus; ACE2-mediated entry; similar imaging findings (bilateral GGO); lymphopenia; progression to ARDS	COVID-19 has a longer and more variable incubation period (2-14 days), more frequent loss of smell and taste, much higher transmissibility (higher R0), and lower overall case fatality rate; SARS-CoV-2 PCR differentiates
Legionella Pneumonia	Atypical pneumonia with high fever, dry cough, no upper respiratory symptoms; diarrhea may be present; elevated LDH and transaminases	Legionella is associated with contaminated water systems (cooling towers, hot tubs) rather than person-to-person spread; hyponatremia is more prominent; Legionella urinary antigen test is positive
Mycoplasma pneumoniae	Atypical pneumonia in a younger patient; dry cough; bilateral interstitial infiltrates	Mycoplasma has an insidious onset (not the abrupt high fever of SARS); associated with bullous myringitis and cold agglutinins; rarely causes ARDS; no epidemiologic link to SARS
Pneumocystis jirovecii Pneumonia (PJP)	Bilateral ground-glass opacities; progressive dyspnea; elevated LDH	PJP occurs in immunocompromised patients (especially HIV with CD4 <200 cells/microL); subacute rather than acute onset; silver stain or DFA of induced sputum is diagnostic

6. Traps and High-Yield Pearls

The most common way students get SARS questions wrong is by failing to prioritize infection control as the first management step. When a vignette describes a febrile patient with respiratory symptoms and a travel or contact history to an affected area, many examinees jump to ordering RT-PCR or starting ribavirin. The correct "next best step" is always to isolate the patient first. Testing comes after isolation, not before.

A second frequent error involves the timing sensitivity of RT-PCR. Students often assume that a negative RT-PCR on day 2 or 3 of illness rules out SARS. It does not. The viral load in upper respiratory specimens peaks during Phase 2 (days 8 to 14), so early testing can yield false negatives. The correct interpretation of a negative early PCR is that the test should be repeated on a different specimen type or at a later time point, and the patient should remain in isolation until SARS is adequately excluded.

A third trap is confusing SARS with MERS or COVID-19 based on the shared coronavirus etiology. All three cause severe lower respiratory illness and can progress to ARDS, but the epidemiologic link is the discriminator. SARS is linked to southern China and the 2003 outbreak period (or laboratory exposure); MERS is linked to the Arabian Peninsula and camel contact; COVID-19 has global distribution. If the vignette gives you a geographic or contact history, use it as the primary differentiating clue.

Finally, students frequently select ribavirin or corticosteroids as the primary treatment. Neither has proven efficacy for SARS in controlled trials. The examinable answer for management is supportive care plus strict infection control. Drug-based therapy is adjunctive at best, and the question stem is typically testing whether you know that no antiviral has been validated, rather than whether you can name one.

The core competency being tested in SARS questions is the ability to recognize a clinical pattern (febrile lower respiratory illness without upper respiratory symptoms, lymphopenia, bilateral ground-glass opacities, and an epidemiologic link), act immediately on infection control, classify the patient using the WHO framework, and sequence the diagnostic workup correctly while understanding the limitations of early testing.

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